Agmatine is an endogenous amine and four carbon guanidine cation that is synthesized in the brain following decarboxylation of L-arginine by arginine decarboxylase (ADC: EC 4.1.1.19 (Li et al., 1994). Recent evidence suggests that brain agmatine is more than a mere metabolic intermediate in a pathway leading to polyamine synthesis (Reis and Regunathan, 2000). For instance, animal studies have revealed agmatine's beneficial effects for treating idiopathic pain (Fairbanks et al., 2000), convulsions (Demehri et al., 2003), and stress-related behaviors (Zomkowski et al., 2002 and Lavinsky et al., 2003).
Additionally, studies have indicated that exogenously-administered agmatine undergoes complex interactions with morphine in vivo to: enhance the analgesic effect of (Kolesnikov et al., 1996); block tolerance to and substance dependence on (Li et al. 1999); and attenuate the symptoms caused by withdrawal from morphine (Aricoioglu-Kartal et al., 1997). It has also been shown that agmatine is neuroprotective if given during the early stages of ischemic brain injury (Gilad et al., 1996).
Although originally identified in the brain as an endogenous neurotransmitter that was bound by imidazoline receptors (Li et al., 1994), agmatine's effects have been primarily ascribed to inhibition of nitric oxide synthase (NOS) (Demady et al., 2001) or blockage of glutamate NMDA receptor channels and other ligand-gated cationic channels (Yang et al., 1999).
Existing technology focuses on the use of agmatine itself or the identification of proteins related to, but distinct from agmatinase. For example, U.S. Pat. No. 6,642,039 B1 describes the identification of a human arginase, and polynucleotides encoding the agmatinase-like arginase.
U.S. Pat. No. 6,544,541 B1 describes the use of various eukaryotic mono(ADP-ribosyl)ation transferases (ADPRT) decoy substrates to treat or prevent proliferative disorders, such as restenosis. Included among these decoy substrates is agmatine.
U.S. Pat. No. 6,150,419 describes the use of agmatine as a treatment for neuropathic pain.
U.S. Pat. No. 5,574,059 describes methods for treating disorders mediated by vascular smooth muscle cell proliferation using antiproliferative compounds. Agmatine is listed as among those compounds useful as part the described treatments.
Thus, there exists a need for compounds that prolong the availability of agmatine. Agmatinase is believed to be the rate-limiting enzyme responsible for regulating the half-life of agmatine in the brain (Sastre et al., 1996). Accordingly, there is a need for compounds that selectively inhibit this enzyme.